Inhibition of NMDA-gated ion channels by bis(7)-tacrine: Whole-cell and single-channel studies

Yu Wei Liu, Jia Lie Luo, Hong Ren, Robert W. Peoples, Yong Xun Ai, Li Jiang Liu, Yuan Ping Pang, Zhi Wang Li, Yifan Han, Chao Ying Li

Research output: Journal article publicationJournal articleAcademic researchpeer-review

14 Citations (Scopus)

Abstract

Bis(7)-tacrine is a novel dimeric acetylcholinesterase inhibitor derived from tacrine, and has been proposed as a promising agent to treat Alzheimer's disease. We have recently reported that bis(7)-tacrine prevents glutamate-induced neuronal apoptosis by antagonizing NMDA receptors. The purpose of this study was to characterize bis(7)-tacrine inhibition of NMDA-activated current by using patch-clamp recording techniques. In cultured rat hippocampal neurons, bis(7)-tacrine inhibited NMDA-activated whole-cell current in a concentration-dependent manner with an IC50of 0.66 ± 0.07 μM. Bis(7)-tacrine produced a gradual decline of NMDA-activated current to a steady-state, but this was not an indication of use-dependence. Also, the slow onset of inhibition by bis(7)-tacrine was not apparently due to an action at an intracellular site. Bis(7)-tacrine, 0.5 μM, decreased the maximal response to NMDA by 40% without changing its EC50. Bis(7)-tacrine inhibition of NMDA-activated current was not voltage-dependent, and was independent of glycine concentration. Results of single-channel experiments obtained from cells expressing NR1 and NR2A subunits revealed that bis(7)-tacrine decreased the open probability and frequency of channel opening, but did not significantly alter the mean open time or introduce rapid closures. These results suggest that bis(7)-tacrine can inhibit NMDA receptor function in a manner that is slow in onset and offset and noncompetitive with respect to both NMDA and glycine. The noncompetitive inhibition of NMDA receptors by bis(7)-tacrine could contribute to its protective effect against glutamate-induced neurotoxicity.
Original languageEnglish
Pages (from-to)1086-1094
Number of pages9
JournalNeuropharmacology
Volume54
Issue number7
DOIs
Publication statusPublished - 1 Jun 2008

Keywords

  • Acetylcholinesterase inhibitor
  • Electrophysiology
  • Glutamate receptor
  • NMDA receptor

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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